Cycloaddition, tetrahydrofuran

The present preparation illustrates a general and convenient irethod for ring contraction of cyclic ketones. The first step is the usual procedure for the preparation of enamines. The second step involves 1,3-dipolar cycloaddition of diphenyl phosphorazidate to an enamine followed by ring contraction with evolution of nitrogen. Ethyl acetate and tetrahydrofuran can be used as a solvent in place of toluene. Pyrrolidine enamines from various cyclic ketones smoothly undergo the reaction under similar reaction conditions. Diphenyl (cycloalkyl-1-pyrrolidinylmethylene)phosphoramidates with 5,6,7, and 15 members in the ring have been prepared in yields of 68-76%. 

Other advances include the construction of seven- and nine-membered rings via the analogous [4-1-3] and [6-1-3] cycloadditions with dienes and trienes respectively. Heterocycles, such as tetrahydrofurans and pyrrolidines, are accessible using carbonyl compounds and imines as substrates. The following discussion is organized around these recent discoveries. It serves to illustrate the versatility and the high degree of selectivity which are some of the distinctive features of the Pd-TMM chemistry. 

TMM cycloadditions to cyclic and conjugated ketones have also been reported (Scheme 2.22) [31]. The steric nature of the substrate does play a critical role in determining product formation. Thus the cyclic ketone (73) produced 55% yield of the tetrahydrofuran, but no cycloadduct could be obtained from the cyclic ketone (74). The enone (75) gave only carbonyl cycloaddition, whereas enone (76) yielded only olefin adduct. Interestingly, both modes of cycloaddition were observed with the enone (77). The ynone (78) also cycloadds exclusively at the carbonyl function [34]. 

Reductive ring opening of the [i-lactam 10 (X = O), obtained by [2 + 2] cycloaddition of chloro-sulfonyl isocyanate and tetraphenylcyclopentadiene followed by treatment with /7-cresol, with sodium hydride in anhydrous tetrahydrofuran yields 3,5,6,7-tetraphenyl-2//-azepin-2-one (11, X = O).41 Surprisingly, similar treatment of the reduced /Mactam 10 (X = H2) is reported to yield 3,5,6,7-letraphenyl-2//-azepine (11, X = H2), the first monocyclic 277-azepine to be isolated and characterized. Physical data for this compound, however, are inconclusive and attempts to reproduce this synthesis have failed.291... 

Catalytic cyclopropanation of alkenes has been reported by the use of diazoalkanes and electron-rich olefins in the presence of catalytic amounts of pentacarbonyl(rj2-ris-cyclooctene)chromium [23a,b] (Scheme 6) and by treatment of conjugated ene-yne ketone derivatives with different alkyl- and donor-substituted alkenes in the presence of a catalytic amount of pentacarbon-ylchromium tetrahydrofuran complex [23c]. These [2S+1C] cycloaddition reactions catalysed by a Cr(0) complex proceed at room temperature and involve the formation of a non-heteroatom-stabilised carbene complex as intermediate. 

The application of 1,3-dipolar cycloaddition processes to the synthesis of substituted tetrahydrofurans has been investigated, starting from epoxides and alkenes under microwave irradiation. The epoxide 85 was rapidly converted into carbonyl ylide 86 that behaved as a 1,3-dipole toward various alkenes, leading to quantitative yields of tetrahydrofuran derivatives 87 (Scheme 30). The reactions were performed in toluene within 40 min instead of 40 h under classical conditions, without significantly altering the selectivi-ties [64]. 

ISOC reaction was employed to synthesize substituted tetrahydrofurans 172 fused to isoxazolines (Scheme 21) [44b]. The silyl nitronates 170 resulted via the nitro ethers 169 from base-mediated Michael addition of allyl alcohols 168 to nitro olefins 167. Cycloaddition of 170 followed by elimination of silanol provided 172. Reactions were conducted in stepwise and one-pot tandem fashion (see Table 16). A terminal olefinic Me substituent increased the rate of cycloaddition (Entry 3), while an internal olefinic Me substituent decreased it (Entry 4). 

The 10 OC route was followed for the synthesis of tetrahydrofurans possessing a y-amino alcohol moiety 247 (Eq. 29) 118]. Aldoximes 21a-f (see also Eq. 3 and Table 2), when heated in benzene in a sealed tube at 110 -120 °C for 6 h, underwent smooth intramolecular cycloaddition to the tetrahydrofuranoisoxazo-lidines 246a-f in 70-83% yield (Eq. 29). This ring closure proceeded stereo-specifically to generate three adjacent stereogenic centers. LAH reduction of 246 b resulted in isolation of stereospecifically functionalized tetrahydrofuran derivative 247b in 75% yield. 

The Michael addition of allyl alcohols to nitroalkenes followed by intramolecular silyl nitronate olefin cycloaddition (Section 8.2) leads to functionalized tetrahydrofurans (Eq. 4.15).20... 

The general procedure used for the synthesis of [l,2,3]triazolo[l,2-tf][l,2,4]benzotriazin-l-5(6//)-dione derivatives 506 is shown in Scheme 86. Ionic 1,3-dipolar cycloaddition of the appropriate azide 503 to ethyl phenylacetates gives l-(2-nitrophenyl)-4-aryl-5-oxo[l,2,3]triazoles 504. Catalytic reduction of these compounds affords the corresponding amines 505. Cyclocondenzation of these amines to the final tricyclic compounds 506 is performed using triphosgene in anhydrous tetrahydrofuran solution at room temperature (Scheme 86) <2005JME2936>. 

A suspension of 414 in aquoeus dioxane was treated with proline 433a and iV-phenyl isatin 432a and the reaction mixture was heated at 80-90 °C overnight. The resin-containing cycloaddition product was reduced in aqueous tetrahydrofuran with lithium borohydride for 12 h at room temperature to afford a mixture of mainly 437 and a trace of 438 unlike in solution phase where in equal amount of 437 and 438 were produced (Scheme 99). 

FIGURE 8.20 Peptides activated at an IV-methylamino-acid residue are postulated to epimer-ize because of the formation of the oxazolonium ion. Evidence for the latter resides in spectroscopic studies,96 and the isolation of a substituted pyrrole that was formed when methyl propiolate was added to a solution of Z-Ala-MeLeu-OH in tetrahydrofuran 10 minutes after dicyclohexylcarbodiimide had been added.95 The acetylenic compound effected a 1,3-dipolar cycloaddition reaction (B), with release of carbon dioxide, with the zwitter-ion that was generated (A) by loss of a proton by the oxazolonium ion. 

For the first time, DFT theory has been applied to a study of diastereofacial selectivity in 1,3-dipolar cycloadditions of nitrones to di-3,4-dimethylcyclobutene. ° The stereochemical outcome of the INAC reactions of nitrones (49) and (52) derived from 3-(9-allyl-D-hexoses is dependent only on the relative configuration at C(2,3), and thus 3-(9-allyl-D-glucose (48) and -o-altrose (threo configuration) afford oxepanes (50) selectively whereas 3-O-allyl-D-allose (51) and -D-mannose (erythro configuration) give tetrahydrofurans (53) and (54) selectively (Scheme 18). frani-2-Methylene-... 

Lewis acid-promoted [3+2] cycloadditions of aziridines and epoxides proceeding via carbon-carbon bond cleavage of three-membered ring heterocycles are demonstrated for the first time. This proposal details plans for extending these initial results into a general synthetic method for the enantioselective synthesis of structurally diverse pyrrolidine- and tetrahydrofuran-containing organic compounds. Expected outcomes of the proposed work will include... 

Dihydro- and tetrahydrofuroisoxazoline rings were constructed by intramolecular cycloaddition of nitrile oxides or nitrones, generated from oximes . Thus, oxime 30 and sodium hypochlorite afforded furoisoxazolines 31 (equation 14). Similarly, furanyl or thienyl oximes 32 in the presence of NaOCl afforded tricyclic products 33 in 35-90% yields (equation 15). Nitrostyrenes (ArCH=CHN02) and various nucleophiles (for example, allyl mercaptan) also generated hydroximoyl chlorides which underwent similar cycloaddition leading to bicycUc tetrahydrothiophene and tetrahydrofuran derivatives ... 

The influence of the size and configuration of various cyclic vinyl carriers (Scheme 6.26) on the stereoselectivity of cycloaddition was studied, and included epoxides, (3-lactams, dioxaborolanes, and dioxans (22). Although the anti preference was maintained in all cases, the conformation of the carrier ring must also be taken into account in order to rationalize the stereoselections observed. The highest diastereomeric ratio was observed with the vinyl-tetrahydrofuran derived from glucose, where the conformational mobility of the carrier ring is substantially locked by an acetonide clamp and one face of the C=C bond is effectively shielded (22,165,215). 

In 1984, a facile synthesis of pyrrolo[3,4-/7]indole (5) as a stable indole-2,3-quinodimethane analogue using an intramolecular azide-alkene cycloaddition-cycloreversion strategy was reported (Scheme 9.2) (3). Treatment of bromo compound 3 with NaNs in aqueous tetrahydrofuran (THF) produced the triazoline 4 via an intramolecular 1,3-dipolar cycloaddition of an intermediate azide. Treatment of the triazoline 4 with p-toluenesulfonic acid (p-TSA) effected 1,3-dipolar cycloreversion of 4 to give pyrroloindole 5 in 82% yield along with diethyl diazomalonate. 

An intramolecular photocyclization approach has been developed for the synthesis of strained tetrahydrofuran and tetrahydropyrrole derivatives from tetronates (Table 1) <2004EJO4582, 2005JOC9798>. The cycloaddition reaction is not sensitive toward the degree of substitution on either reactive center and produces a single diastereoisomer in all cases (Equation 42). 

Carbonyl ylides were first reported to undergo intramolecular 1,3-dipolar cycloaddition to C—C double bonds in 1980.121 New polycyclic ring systems containing a tetrahydrofuran are formed. Dipola-... 

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